xc2xa7 1.1 Field of the Invention
The present invention relates to the field of polymers and, in particular, to polymerization, such as the photoinitiated polymerization of water soluble reactive monomers by radicals.
xc2xa7 1.2 Related Art
A first aspect of the present invention concerns polymerization and the cage effect. These topics are introduced in xc2xa7xc2xa7 1.2.1 and 1.2.2, respectively, below. A second aspect of the present invention concerns hydrogels, which may be produced by the first aspect of the invention. Hydrogels are introduced in xc2xa7 1.2.3 below.
xc2xa7 1.2.1 Photoinitiated Polymerization
The field of photointiated polymerizations is a subject of intense scientific and industrial study. Many applications such as photoresists, flexographic printing plates, photopolymerizable inks, coatings, and adhesives have been widely used. Yet many aspects of photopolymerization are incompletely understood and not subject to the utmost possibility of control.
Water-based photopolymerizations have a special advantage in protection of the environment. The development of water-soluble photoinitiators is under active development and new methods need to be created to control such photopolymerizations.
xc2xa7 1.2.2 The xe2x80x9cCage Effectxe2x80x9d
The concept of the xe2x80x9ccage effectxe2x80x9d was introduced in 1934 to explain why the efficiency of I2 photodissociation was less in solution than in the gas (Frank, J.; Rabinowitch, E., Trans. Faraday Soc., 30, 120 (1934). This article is incorporated herein by reference.). Frank and Rabinowitch proposed that the solvent temporarily encapsulates the reactive iodide radical atoms in a solvent cage causing the radicals to remain as colliding neighbors before they either recombine or diffuse apart.
The cage effect has been widely used to explain many fundamental reaction phenomena; for example, magnetic isotope effects (Turro, N. J., J. Proc. Nat. Acad. Sci., 80, 609 (1983). Lott, W. B.; Chagovetz, A. M.; Grissom, C. B., J. Am. Chem. Soc., 117, 12194 (1995). These articles are incorporated herein by reference.), chemically induced dynamic nuclear polarization effects (Closs, G., J. Am. Chem. Soc., 91, 4552 (1969). This article is incorporated herein by reference.), rate-viscosity correlations (Tanner, D. D.; Meintzer, C. P.; Tsai, E. C.; Oumar-Mahamat, H., J. Am. Chem. Soc., 112, 7369 (1990). This article is incorporated herein by reference.), variations in products and yields as a function of the medium (Koenig, T.; Deinzer, M.; Hoobler, J. A., J. Am. Chem. Soc., 93, 938 (1971). This article is incorporated herein by reference.) and variations in quantum yields as a function of the medium (Abram, I.; Milne, F.; Steel, C., J. Am. Chem. Soc., 86, 745 (1969). This article is incorporated herein by reference.). The cage effect arising from solvent is important in explaining the kinetics including the initiation, propagation, and termination steps, of radical polymerization reactions. (Odian, G., Principles of Polymerization: 3rd ed., (Wiley-Interscience: New York, 1991). Bosch, P.; Mateo, J. L.; Serrano, J., J. Photochem. Photobiol. A, 103, 177 (1997). Tefera, N.; Weickert, G.; Westerterp, K. R., J. Appl. Polym. Sci., 63, 1663 (1997). Wolff, E. -H. P.; Bos, A. N. R., Ind. Eng. Chem. Res., 36, 1163 (1997). These works are incorporated herein by reference.)
Since supramolecular complexation became an intense field of study, cage effects have been one of the most important issues in this field. For example, cyclodextrin has been used as a cage in the study of photochemical reactions of dibenzyl ketones. (Rao, B. N.; Turro, N. J.; Ramamurthy, V., J. Org. Chem., 51, 460 (1986). Rao, B. N.; Syamala, M. S.; Turro, N. J.; Ramamurthy, V., J. Org. Chem., 52, 5517 (1987). These articles are incorporated herein by reference.) To make a long-lasting cage, people have tried to modify cage structures to cause more interactions between the host (cage) and the guest (radical pair). Among these are hydrophobic interactions in aqueous solutions.
Recently, many researchers have focused on the study of radical recombination in micelle systems. (Gould, I. R.; Zimmt, M. B.; Turro, N. J.; Baretz, B. H.; Lehr, G. F., J. Am. Chem. Soc., 107, 4607 (1985). Wu, C.-H.; Jenks, W. S.; Koptyug, I. V.; Ghatlia, N. D.; Lipson, M.; Tarasov, V. F.; Turro, N. J., J. Am. Chem. Soc., 115, 9583 (1993). These articles are incorporated herein by reference.) Turro et al. have investigated the effects of systematic changes in radical structure (hydrophobicity) and micelle structure. (Turro, N. J.; Wu, C.-H., J. Am. Chem. Soc., 117, 11031 (1995). This article is incorporated herein by reference.)
xc2xa7 1.2.3 Hydrogels
Gels are chemically or physically cross-linked networks of polymers that can be swollen by liquids. Among the gels, a hydrogel is a network of hydrophilic polymers in which a large amount of water is present. Because of their relatively high biocompatibility, research on hydrogels has been focused on biomedical applications. (Peppas, N. A. e. a., Hydrogels in Medicine and Pharmacy; Properties and Applications (CRC Press, Boca Raton, Fla., 1987) Vol. 3. This work is incorporated herein by reference.) Artificial skin (Chardack, W. N.; Brueske, D. A.; Santomauro, A. p.; Fazekas, G., Ann. Surg., 155, 127 (1962). DeRossi, D., Polymer Gels (Plenum Press New York, 1991). These works are incorporated herein by reference.) or contact lenses (Wichterle, O.; D., L., Nature, 185, 117, (1960). Wichterle, O.; D., L. U.S. Patent (1961). These works are incorporated herein by reference.) have a long history in the applications of the hydrogels. Recently, drug delivery system using hydrogels became a very fast growing research area. (Peppas, N. A.; Bures, P.; Leobandung, W.; Ichikawa, H., Eur. J. Pharma. Biopharm, 50, 27, (2000). This article is incorporated herein by reference.)
xc2xa7 1.2.3.1 Physical Hydrogels Differ from Covalently Crosslinked Hydrogels
In physical gels, a gelation occurs through van der Waals or hydrogen bonding or other noncovalent interactions between chains. (xe2x80x9cThermoreversible Gelation of Polymers and Biopolymers, by J. -M. Guenet, 1992, Academic Press. Incorporated herein by reference.) Physical gels require high cooperativity to be stable. For example, the energy involved in van der Waals interaction can be small compared to kT. Consequently, these gels can be reversible.
Most physical hydrogels are biopolymers, such as gelatin gels (Katz, J. R.; Derksen, J. C.; Bon, W. F., Rec. Trav. Chim. Pays-Bas, 50, 725, (1931). This article is incorporated herein by reference.) and polyssacharide gels (Anderson, N. S.; Campbell, J. W.; Harding, M. M.; Rees, D. A.; Samuel, J. w. B., J. Mol. Biol., 45, 85, (1969). This article is incorporated herein by reference.). Gelatin gels (Petzron, I.; Djabourov, M.; Bosio, L.; Leblond, J., J. Polym. Sci. polym. Phys. Ed., 28, 1823, (1990). This article is incorporated herein by reference.) consist of triple helices. Polysaccharide gels are known to be composed of double helices (Hermansson, A. M., Carbohydr. Polym., 10, 163, (1989). This article is incorporated herein by reference.).
There are few examples of physical gels made by synthetic polymers. Poly(vinyl alcohol) (PVA) gels are probably the first system of this kind ever to be studied. (Sone, Y.; Hirabayashi, K.; Sakurada, I., Kobunshi Kagaku 10, 1, (1953). Kominami, T.; Naito, R.; Odanaka, H., Kobunshi Kogaku, 12, 218, (1955). These articles are incorporated herein by reference.) Very intensive studies of PVA gels have been performed (Peppas, N. A.; Merrill, E. W., J. Polym. Sci. Polym Chem. Ed., (1976). Finch, C. A. PVA-Properties and Applications (John Wiley and Sons: New York, 1973). These works are incorporated herein by reference.), including studies of chemically cross-linked PVA gels. (Takamura, T.; Takayarna, G.; Ukida, G., J. Appl. Polym. Sci., 9, 3215, (1965). This article is incorporated herein by reference.) Physical gels are generally xe2x80x9cweakerxe2x80x9d than chemical gels. For example, the physical cross-linking of a gel can be destroyed by adding large amounts of solvent.
xc2xa7 1.2.3.2 Intelligent Hydrogels
The first responsive polymer gel was created by Katchalsky in 1949 by cross-linking water-soluble polyelectroyltes to form gels that swelled and shrank in response to changes in solution pH. (Katchalsky, A., Experientia, 5, 319 (1949). This article is incorporated herein by reference.) That gel showed a gradual response to changes in pH. Tanaka (Tanaka, T., Phys. Rev. lett., 40, 820 (1978). This article is incorporated herein by reference.) observed a sharp phase transition in ionized polyacrylamide gels. Since this work, the field of responsive gels has expanded dramatically.
The relatively large and sharp chemical or physical changes of hydrogels in response to small chemical or physical changes has led to some hydrogels being called xe2x80x9cintelligentxe2x80x9d gels. (Hoffman, A. S., Macromol. Symp., 98, 645 (1995). This article is incorporated herein by reference.) Response of the hydrogel to environmental changes, such as temperature (Hirose, H.; Shibayama, M., Macomolecules, 31, 5336 (1998). This article is incorporated herein by reference.), pH (Osada, Y., Adv. Polym. Sci., 82, 1 (1987). This article is incorporated herein by reference.), solvents, electric fields (Kwon, I. C.; Bae, Y. H.; Kim, S. W., Nature, 354, 291 (1991). This article is incorporated herein by reference.), light (Suzuki, A.; Tanaka, T., Nature, 346, 345 (1990). This article is incorporated herein by reference.), or even a specific protein, (Miyata, T.; Asami, N.; Uragami, T., Nature, 399, 766 (1999). This article is incorporated herein by reference.) can cause drastic changes in phase, shape, or surface energy. These characteristics of the hydrogel have been utilized for drug release systems. (Peppas, N. A.; Bures, P.; Leobandung, W.; Ichikawa, H., Eur. J. Pharma. Biopharm, 50, 27 (2000). This article is incorporated herein by reference.)
Hydrogen bonding is known as one of the fundamental forces to control the behavior of responsive gels. PMA and PEG are well known for forming polymer complexes by hydrogen bonding in solution. (Osada, Y., Adv. Polym. Sci., 82, 1 (1987). Abe, K.; Koide, M.; Tsuchida, E. Macromolecules, 10, 1259 (1977). Bedner, B.; Morawetz, H.; Shafer, J. A., Macromolecules, 17, 1634 (1984). Iliopoulos, I.; Audebert, R. A., Macromolecules, 24, 2566 (1991). These articles are incorporated herein by reference.) PAAm and PAA are also known as polymers that interact by intra- or intermolecular hydrogen-bonding. (Silberberg, A.; Eliassaf, J.; Katchalsky, A., J. Polym. Sci., 23, 259 (1957). Wang, Y.; Morawetz, H., Macromolecules, 22, 164 (1989). These articles are incorporated herein by reference.) Katano et al. (Katono, H.; Maruyama, A.; Sanui, K.; Ogata, N.; Okano, T.; Sakurai, Y., J. Controlled Release, 16, 215 (1991). This article is incorporated herein by reference.) have studied the temperature dependence of polymer solubility on the PAA, PAAm in water systems. In aqueous solutions of PAAm-PAA and in related polymer solutions, they observed temperature dependent solubility of the polymer. At low pH, they observed turbidity in the solution. They concluded that the complexation of PAA and PAAm is due to the intermolecular hydrogen bonding between acid and amide groups (See FIG. 13.) and that this might cause precipitation.
Aoki et al. also have studied hydrogen-bonds between PAA and poly(N,N-dimethylacrylamide) (PDMAAm) in interpenetrating polymer network. (Aoki, T.; Masahiko, K.; Katono, H.; Sanui, K.; Ogata, N.; Okano, T.; Sakurai, Y., Macromoleecules, 27, 947 (1994). This article is incorporated herein by reference.) In their paper, they proposed that PAA-PDMAAm gel has more efficient bonds between acid and amide than PAA-PAAm gel based on the inter- and intramolecular hydrogen-bonded complexes.
Thermo-sensitive hydrogels are mostly made of PAAm derivatives with hydrophobic groups, because the hydrophobic interaction, which is a driving force for the gel shrinking, can be promoted by increase of the temperature. Glucose-sensitive hydrogels that are made of pH-sensitive polymers have been developed. (Klumb, L. A.; Horbett, T. A., J. Control. Release, 27, 95 (1993). Ishihara, K.; Kobayashi, M; Shionohara, I., Makromol. Chem. Rapid Commun., 4, 327 (1983). These articles are incorporated herein by reference.)
To achieve fast responsive-gels, many researchers have explored recently types of hydrogels other than random cross-linked polymers, i.e., graft or block copolymers (Jeong, B.; Bae, Y. H.; Lee, D. S.; Kim, S. W., Nature, 388, 860 (1997). This article is incorporated herein by reference.). Compared to random copolymers, researchers found a higher sensitivity in the response of graft copolymers toward varying stimuli. (Hoffman, A. S.; Chen, G. H., Nature, 373, 49 (1995). Chen, G.; Hoffman, A. S., Nature, 373, 49 (1995). Hassan, C. M.; Doyle III, F. J.; Peppas, N. A., Macromolecules, 30, 6166 (1997). These articles are incorporated herein by reference.) A graft copolymer, which has pH-sensitive (acrylic acid) and temperature-sensitive (N-isopropyl acrylamide) components, has developed by Chen and Hoffman. (Chen, G.; Hoffman, A. S., Nature, 373, 49 (1995). This article is incorporated herein by reference.) Another graft copolymer, but chemically cross-linked gel, of PMA and poly(ethylene glycol) (PEG) has been developed as a pH-sensitive gel by a research group in Purdue University. (Hassan, C. M.; Doyle III, F. J.; Peppas, N. A., Macromolecules, 30, 6166 (1997). Klier, J.; Scranton, A. B.; Peppas, N. A., Macromolecules, 23, 4944 (1990). These articles are incorporated herein by reference.)
Given their growing number of important applications, there is a need to develop new hydrogels.
The present invention exploits a cage effect in poly(methacrylic acid) PMA, or in other polyelectrolytes with pH, salt and/or solvent dependent hydrophobic properties with guest radicals produced photochemically to control free radical polymerization. In addition, the invention includes polyelectrolytes with hydrophobic properties that are subject to addition of water miscible solvents to the water solution of the invention. Such solvents could be an alcohol. If alcohol is added to such a water solution, it could act in the same way as increasing the pH and weakening the hydrophobic effect so as to effectively open the cage and release the radicals to cause polymerization of a waiting monomer in the solution. The present invention may therefore use the hydrophobic property of PMA to produce an effective pH-responsive cage for initiating radicals in aqueous solution thereby providing a free radical polymerization that can be controlled by pH, or by adding salt, or solvent to the aqueous solution. The present invention may therefore use addition of certain solvents to water solutions to alter the hydrophobic properties of PMA without substantial change of pH. Salt may also play this role.
In one embodiment of the present invention, a photoinitiator labeled PMA is synthesized with a small proportion of the initiating group (PI-PMA) (See FIG. 2 (e)) to enable a pH-triggered photopolymerization of water soluble monomers. For this strategy, hydrophobic properties of the radical pairs generated from the photoinitiator permit such radical pairs to remain in the cage long enough to recombine before they escape and initiate the polymerization.
The present invention permits the production of, via a pH-gated photopolymerization, a graft copolymer of PMA with PAAm by the polymerization of acrylamide initiated by a photoinitiator appended to PMA. This polymer forms a hydrogel containing a large amount of water for the amount of polymer present. The physically cross-linked network may be formed by inter-chain hydrogen bonding in this system. In place of acrylamide, other water soluble monomers may also be used in this invention for formation of hydrogels. For example, with N,N-dimethylacrylamide and N-isopropylacrylamide may be used. Other hydrogen bonding water soluble monomers, such as CH2xe2x95x90CHxe2x80x94COOCH2CH2N(CH3)2 and other water soluble free radical polymerizeable monomers as are well known in the art of polymerization, may also be used.